Isosteric replacements for benzothiazoles and optimisation to potent Cathepsin K inhibitors free from hERG channel inhibition.
Bioorg Med Chem Lett
; 22(17): 5563-8, 2012 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-22858142
ABSTRACT
The discovery of nitrile compound 4, a potent inhibitor of Cathepsin K (Cat K) with good bioavailability in dog is described. The compound was used to demonstrate target engagement and inhibition of Cat K in an in vivo dog PD model. The margin to hERG ion channel inhibition was deemed too low for a clinical candidate and an optimisation program to find isosteres or substitutions on benzothiazole group led to the discovery of 20, 24 and 27; all three free from hERG inhibition.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzotiazóis
/
Canais de Potássio Éter-A-Go-Go
/
Catepsina K
/
Nitrilas
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article